Abstract
Interference of Ras signaling deregulates thymocyte development in mouse models. However, the role of Ets-2, a transcription factor that is phosphorylated on a critical threonine residue (Thr-72) by the Ras/MAPK pathway in thymocyte development, has not been defined. Transgenic mice overexpressing a phosphomutant Ets-2 (T72A) in the thymus displayed reduced thymus size associated with a 60-80% reduction in thymocyte populations. The transgenic mice exhibited a 20-fold increase in a c-Kit(+) CD4(+) CD8(+) CD3(-) population and a 5-fold increase in a unique CD5(low) population associated with a partial developmental block at the DN2-DN3 stage of thymocytes. Transgenic thymocytes exhibited increased apoptosis, and overexpression of Bcl-2 rescued the hypocellularity and associated thymocyte developmental block in double transgenic mice. The observed defects in these mice are not dependent on Ets-1 expression. These studies implicate for the first time a stage-specific Ets-1-independent regulatory role for Ets-2 in early thymocyte development and survival.
Highlights
The transcription factor Ets-2 is highly expressed in mouse thymocytes
Ras-mediated Activation of Ets-2 in T-cells Is Dependent on Threonine 72—In a variety of cell types Ets-2 is regulated by the Ras-dependent MAPK ERK (10, 11)
To determine whether Ets-2 is regulated in a Ras-dependent mechanism in T-cells, Jurkat T-cells were transiently cotransfected with either wild type Ets-2 or a phosphomutant Ets-2T72A, along with a constitutively active Ras, and a luciferase reporter gene driven by the Ets-2-dependent urokinase plasminogen promoter (Fig. 1) (10)
Summary
The transcription factor Ets-2 is highly expressed in mouse thymocytes. Results: Expression of a phosphomutant Ets-2 (T72A) in mouse thymus severely alters T-cell development. A transgenic mouse model that expressed a dominant-negative Ras (H-rasN17) in thymocytes demonstrated that disruption of TCR2-mediated signaling impaired thymocyte-positive selection (2). Subsequent mouse models and experiments have demonstrated a role for MEK (3, 4) and ERK (5–9) in thymocyte-positive and -negative selection and maturation. These models have provided invaluable information on the importance of CD3-mediated activation of the Ras signaling pathway in thymocyte development. Despite these numerous mouse models and in vitro experiments, there is limited infor-
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